DE1593350C - 3.20 Diono 17 alpha methyl 19 nor pregna 4.9 dien and process for its preparation - Google Patents

Description

This compound can be prepared according to the invention in the following way: The 3-ChIOr-S-OXO-17a-methyl-20-benzoyloxy-4,5-seco-19-nor-pregna-2,9-diene II is saponified to the 3 - Chlorine - 5 - oxo-17a - methyl - 20 - hydroxy - 4,5 - seco -19 - nor - pregna-2,9-diene III, oxidizes this to 3-chloro-5,20-dioxo-17a - methyl - 4,5 - seco -19 - nor - pregna - 2,9 -diene IV, the vinyl chlorine of which is hydrolyzed in an acidic medium, the S ^^ O-trioxo-na-methyl-4,5-seco-19-nor formed -pregna-9-en V is cyclized with the aid of an alkaline agent.
The F i g. 1 explains these reactions.

H, C

OCOQH ₅
CH ₃

II

III

IV

Fig.

The starting product of this production method, the 3 - chloro - 5 - oxo - 17α - methyl - 20 - benzoyloxy-4,5 - seco - 19 - nor - pregna - 2,9 - diene II, represents an intermediate product in the manufacture of 3,20-dioxo-17a-methyl-19-nor-pregna-4,9, ll-triene and its production is in the German Offenlegungsschrift 1 468 940.

The 3.20 - dioxo - 17a - methyl - 19 - nor - pregna-4,9-diene I can also according to the present Invention also based on 3-MeUiOXy ^ O-OXo-19-nor-pregna-l, 3,5 (10), 16-tetraene can be obtained. This "product is in J. Chem. Soc. 364 (1962) described.

This production method proceeds as follows: The double bond in the 16-, 17-position is reduced des 3 - methoxy -10 - oxo -19 - nor - pregna -1,3,5 (10), 16-tetraene with simultaneous alkylation using

C = O

CH, O

of an alkali metal and a methyl halide to form the S-methoxy-na-methyWO-oxo - ^ - norpregna-l, 3,5 (10) -triene, reduces this according to the method of D j e r a s s i with an alkali metal in the presence of ammonia, the 3-methoxy - 17a - methyl - 20 - hydroxy -19 - nor - pregna-2,5 (10) -diene obtained, which is obtained with formation of the 3-oxo-17a-methyl-20-hydroxy-19-nor-pregna-5 (10) -enes hydrolyzed with a dilute acid, the latter compound is oxidized with an acidic oxidizing agent, where the S ^ O-dioxo-na-methyl - ^ - norpregna-5 (10) -en "is obtained, and this compound brominates with bromine and pyridine and cleaves therefrom subsequently hydrogen bromide, the sought S ^ O-dioxo-na-methyl-W-nor-pregna-4,9-diene is formed. F i g. 2 illustrates the reactions of this preparation method.

C = O

IIA

ΠΙΑ

VA

CH ₃ O

IVA

VIA

Fig.

example 1

Production of the S ^ O-Dioxo-na

pregna-4,9-diensI (Fig. 1)

Level a

19-nor-pregna-2,9-diene III

2. g of 3-chloro-5-oxo-17α-methyl-20-benzoyloxy-4,5-seco-19-nor-pregna-2,9-dieneII are added to 6 cm ^{3 of} anhydrous methanol. ^{50 cm 3 of} a 1 N methanolic potassium hydroxide solution are added to the resulting solution. The reaction mixture is then refluxed for 10 hours while stirring under a nitrogen atmosphere.

After cooling, it is poured into ice water and extracted with methylene chloride. One wins the organic phase, washed with water until the washing water is neutral, then dried and evaporated to dryness in vacuo.

The residue obtained shows up after chromatography. Magnesium silicate and elute with methylene chloride with 0.5% acetone the 3-chloro-5 - oxo - 17a - methyl - 20 - hydroxy - 4,5 - seco -19 - norpregna-2,9-diene III, which is used as it is for the next stage of the synthesis.

The connection has not yet been described in the literature.

Stage B stirred at ambient temperature for 272 hours, then filtered and extracted with methylene chloride.

The organic phase is recovered and washed with water until the washing water is neutral, then dried and evaporated to dryness in vacuo. The 3-chloro-5,20-dioxo-17a-methyl-4,5-seco-19-nor-pregna-2,9-diene is obtained IV, which is used as it is for the next stage of the synthesis.

The connection has not yet been described in the literature.

Level C

pregna-2,9-diene IV

1 g of 3-chloro-5-oxo-17α-methyl-20-hydroxy-4,5-seco-19-nor-pregna-2,9-diene III is added to 100 cm ^{3 of} anhydrous acetone.

The resulting solution is ^{cooled to about 0 °} C. with stirring under a nitrogen atmosphere, and 3 cm ^{3 of} a chromium-sulfuric acid solution, prepared from 1 g of chromium trioxide, 10 cm ^{3 of} water and 1 cm ^{3 of} sulfuric acid, are added over the course of 30 minutes. After the addition of an aqueous saturated sodium bicarbonate solution, the reaction mixture becomes 9-enV

5 cm ^{3 of} sulfuric acid are ^{cooled to about 0 °} C. and a solution of 1 g of 3-chloro- is added very slowly with stirring under a nitrogen atmosphere. 5.20 - dioxo - 17a - methyl - 4.5 - seco -19 - nor - pregna-2,9-diene IV in 2 cm ^{3 of} methylene chloride.

After the addition, the mixture is stirred for about 10 minutes at about 3 ° C., then the reaction mixture is poured into a mixture of 60 cm ^{3 of} methylene chloride and an ice-cold aqueous sodium bicarbonate solution. The organic phase is separated off, washed with water, dried and evaporated to dryness in a vacuum.

The residue obtained gives after chromatography on magnesium silicate and the Elute the 3,5,20-trioxo-17a-methyl-4,5-seco-19-nor-pregna-9-ene with methylene chloride with 2.5% acetone V, which is used as it is for the following stage of the synthesis.

The connection has not yet been described in the literature.

Level D
3,20-Dioxo-17a-methyl-19-nor-pregna-4,9-dieneI

a) Production of sodium t-amylate
2.8 g of sodium are placed in 40 cm ^{3 of} anhydrous toluene under a nitrogen atmosphere and the mixture is heated to reflux. You give up

5 6

with stirring 12.5 cm ³ anhydrous t-amyl alcohol water until the washing water is neutral

to and holds 19 ¹ Z ₂ hours at reflux. Wash, cool, dry over sodium sulfate, filter and

and receives a 1.48 N sodium t-amylate solution. evaporated to dryness. 16.80 g of raw

product ΠΙΑ, which by dissolving in acetone on the back

b) cyclization _{5 fluß uivd} recrystallization in the heat and in

800 mg of 3,5,20-trioxo-17a-methyl- is added which is purified in the cold. The 3-methoxy-

4,5-seco-19-nor-pregna-9-en V in 20 cm ³ anhydrous 17a-methyl-20-oxo-19-nor-pregna-l, 3,5 (10) -triene ΠΙΑ.

Toluene with stirring under a nitrogen atmosphere. The connection is not yet in the literature

After cooling to about 0 ^° C., 0.8 cm ³ are given,

the 1.48 n-sodium t-amylate solution prepared above io stage B

to, adds 4 cm ^{3 of} toluene and stirs the reaction,, ". . _. _{,,, n}

mixture 6 hours. Then add 0.1 cm ^{3 of} vinegar- S-methoxy-na-methyWO-hydroxy - ^ - nor-

acid and 8 cm ^{3 of} toluene and then extracted with pregna-2,5 (10) -diene IVA

Methylene chloride. "A solution is added to 500 cm ^{3 of ammonia}

The organic phase is obtained, the <5 of 20g S-methoxy-na-methyl ^ O-oxo - ^ - nor-

one with water until the washing pregna-l, 3,5 (10) -triene IHA in 400 cm ³ tetrahydro-

water washes, dries and furan in a vacuum to dryness and adds 10 cm ^{3 of} ethanol. The interior

evaporates. temperature is lowered to about -35 ° C. Then there

The residue obtained gives 2.15 g of lithium after Ch * o-man under an inert atmosphere

matograph on magnesium silicate and ■ the ²⁰ , stir for 15 minutes, add 10 cm ^{3 of} ethanol and

Elute with methylene chloride with 2.5% acetone, add another 2.150 g of lithium, stir for 15 minutes,

3,20-Dioxo-17 «-methyl-19-nor-pregna-4,9-diene I; gives 30 cm ^{3 of} ethanol and then 2.150 g of lithium

F. = 106 ⁰ C, [«]? = -270 ° ± 4.5 (c = 0.4%, etha to. After 30 minutes at -35 ° C, 30 cm ³ λ

nol). "Ethanol too. The ammonia is evaporated by

The product precipitates in the form of prisms, which 25 is the temperature brought to +20 ⁰ C, then

in alcohol, ether, acetone, benzene and chloroform are added 500 cm ^{3 of} water and extracted with

are soluble. · Ether. The aqueous phase becomes after the etherification

'deducted. The united ether phases become with

UV spectrum (ethanol): washed with water, dried over sodium sulfate,

? _imax at 214 ηΐμ,. · ε = _r 6 330 30 filtered and distilled to dryness. You get

Infl. at 235 ηΐμ, ε = 4,900 the 3-methoxy-17α-methyl-20-hydroxy-19-nor-

. I ₁ ^ _x at 302 ηΐμ, ε = 20 800 pregna-2,5 (10) -dien IVA, which one as it arises,

λ ι * r * χι r> nn λί \ used for the following stage.

Analysis: C ₂ IH ₂₈ O ₂ (312.43). _. ,. ^ö . . . ....., ■, ■ *

τ, u I poftTi unmo / ^The connection is not yet in the literature

Calculated ... C 80.72, H 9.03%; 35 described

found C 80.6, H 8.9%.

The connection is not yet _Λ , _Λ “in the literature. ,,

described. S-Oxo-no-methyl-JO-hydroxy-W-nor-pregna-

5 (10) -en VA

B e 1 s ρ ie 1 2 _{40 20 g of the} compound IVA are dissolved in 35 cm ³

Preparation of the 3,20-dioxo-17ct-methyl-19-nor- acetone and stir for 15 minutes at ambient temperature

pregna-4,9-diens I (Fig. 2) temperature. 300 cm ^{3 of} acetic acid are then added

Stage A 25% water, stir for 3 hours and pour the remainder

S-Metnoxy-Ha-methyl ^ O-oxo - ^ - nor-pregna-action mixture in a water-ether mixture WO, nflifflf TTTδ ^{45 NaCN to} l ° ^{min runrt} · ^The aqueous phase Λ l, j, 5 ( lU) -tnen HlA _{is deducted after the} / uisäthern. The etherin 11 ammonia cooled to -70 ° C brings phases with an aqueous sodium bicarman with stirring and in an inert atmosphere bonate solution and then washed with water, over 1.150 g of lithium. The mixture is stirred for 15 minutes, then sodium sulphate is dried, filtered and ether is added to dryness, while the temperature is distilled at about 50. The 3-oxo-17a-methyl-20-hy -— 75 ° C. is obtained, as well as 20 g of S-methoxy ^ O-oxo - ^ - nor- droxy-19-nor-pregna-5 (10) -en VA, which is used for the next stage like pregna-1, 3,5 (10), 16-tetraene IIA and leaves it under stan-
Stirring slowly and in an inert atmosphere. In the literature, the compound has not yet stood at -75 ° C for 2 hours. Then 160 cm ³ are given.
Add methyl iodide, stir for 2 hours at -75 ° C, 55 stage D
the ammonia evaporates, adds 11 water. and. .
withdraws the aqueous phase after the etherification. 3,20-Dioxo-17a-methyl-19-nor-pregna-5 (10) -en VIA

The combined ether phases are mixed with 20.5 g of the compound VA with water under nitrogen

Washed until the wash water is neutral, dissolved over and with stirring in 615 cm ^{3 of} acetone, the

Sodium sulfate, filtered and concentrated to dryness ^6o solution is cooled to -20 ° C, then it is

distilled. 21 g of product are obtained, which are added in 21 cm ^{3 of} a dilute solution containing 5.7 g of chromium

210 cm ^{3 of} ethanol dissolves under reflux. Acid anhydride and 4.8 cm ³ concentrated sulfur

21 cm ^{3 of} acetic acid and 21 g of Gerard's reagent T, containing acid, left for 1 hour with stirring at about

stir I ¹ Z ₂ hours under nitrogen at reflux, stand -10 ° C and pour the solution into 21

Allow to cool to ambient temperature and pour ⁶ 5 ice-water mixture. Extract with benzene,

the reaction mixture in 1050 cm ^{3 of} water, then the combined organic phases are washed with water,

155 cm ^{3 of} 2 η sodium hydroxide solution are added and the mixture is then extracted with a saturated sodium bicarbonate solution

with ether. The combined ether phases are dried over with and finally again with water

IO

Magnesium sulfate and distilled to dryness. 20.40 g of crude product are obtained, which is purified by chromatography on magnesium silicate, eluting with benzene with 2.5% acetone and by recrystallization from isopropyl ether. The 3,20-dioxo-17a-methyl-19-nor-pregna-5 (10) -en VIA is obtained. ¹

The connection has not yet been described in the literature.

Level E.
3,20-Dioxo-17a-methyl-19-nor-pregna-4,9-diene I.

With stirring and under nitrogen, 8.50 g of the compound VI are dissolved in 85 cm ^{3 of} pyridine, the mixture is cooled to 0 ^° C., 16.3 cm of ^{J of} a 29% bromine solution in methanol are added, and the mixture is stirred at 0 ^° C. for a further 30 minutes, brings to ambient temperature and lets stand with stirring for 16 hours. The solution is poured into 850 cm ^{3 of} an ice-water mixture, 82 cm ^{3 of} hydrochloric acid are added and the mixture is extracted with methylene chloride. The combined organic phases are washed with water until the wash water is neutral, dried over magnesium sulfate and distilled to dryness. 8.480 g of crude product are obtained, which are purified by recrystallization from isopropyl ether. Are thus obtained 5,810 g of 3,20-dioxo-17a-methyl-19-nor-pregna-4.9-diene I having a melting point = 106 ⁰ C, which is identical to that obtained according to Example 1 product.

The compound I has interesting pharmacological properties. In particular, she has one significant progestomimetic effect.

It can be used to treat amenorrhea, hypermenorrhea, metrorrhagia, menorrhagia, sterility, Miscarriage, all hyperfollicular hormone manifestations of nervous and psychological symptoms, both associated with hypogalactic phenomena as well as more generally with all disorders which causes luteohormone insufficiency can be used.

The 3.20 - dioxo - 17 «- methyl - 19 - nor - pregna-4,9-diene is used orally, perlingually, transcutaneously or rectally.

It can be in the form of injectable solutions or suspensions, in ampoules and conditioned in vials for repeated use, in the form of tablets, coated tablets, sublingual tablets, of gel preparations, emulsions and suppositories.

The usable dosage ranges between 2 and 20 mg per day for adults.

The pharmaceutical formulations, such as injectable solutions or suspensions, tablets, Coated tablets, sublingual tablets, gel preparations, emulsions and suppositories are after usual process.

Pharmacological investigation of the compound obtainable according to the invention

55

60

Determination of progestomimetic activity
1. Orally

The progestomimetic activity of 3,20-dioxo-17a-methyl-19-nor-pregna-4,9-diene is determined according to the test of Clauberg, which is carried out on non-sexually capable rabbits previously administered by the administration of estradiol benzoate in the course of 5 days have been sensitized by the subcutaneous route with a daily dose of 10 γ.

The compound obtainable according to the invention is used in solution in olive oil with an addition of 5% benzyl alcohol and administered orally for 5 days in doses of 5, 10 and 20 γ per day.

The animals are sacrificed the next day, and the tip-like proliferation is established on uterine sections of the endometrium, which is characteristic of the progestomimetic effect. the The experiment is compared with the 3,20-dioxo-6'-chloro-17a-acetoxy-pregna-4,6-diene carried out, which is administered in the same solvent and in the same doses.

Expressed in MacPhail units, one obtains. following results:

Orally administered products
daily dose in γ

3,20-Dioxo-17a-methyl-19-norpregna-4,9-diene

3.20-DiOXO-Oa-ChIOr-

17a-acetoxy-pregna-4,6-diene

MacPhail units

5 10 20
0.4 2.0 2.6
1.6 2.0 2.0

It can be seen from the results that the compound obtainable according to the present invention is applied to oral Weg has a progestomimetic activity essentially that of 3,20-dioxo-6'-chloro-17'-acetoxy-pregna-4,6-diene is equal to.

2. By subcutaneous route

The experiments are carried out subcutaneously under the same experimental conditions. The compound obtainable according to the invention and the 3,20-DiOXO-Oa-ChIOr-Ha-acetoxy-pregna-4,6-diene are dissolved in olive oil with the addition of 5% benzyl alcohol in doses of 1.56, 3.12 and 6.25 γ administered per day.

The results obtained are summarized in the following table and in MacPhail units expressed.

MacPhail unit 3.12 rush Subcutaneously administered Pro products, daily dose in γ 1.56 2 6.25 3,20-dioxo-17a-methyl- 19-nor-pregna-4,9-dien ... 0.7 2.5 3.20-DiOXO-Oa-ChIOr- 2.4 Πα-acetoxy-pregna- 4.6-dien 1.0 2.4

These results show that the inventive compound obtainable at the subcutaneous administration has a progestomimetic activity to that of the 3,20-dioxo-6 '-chloro-17-acetoxypregna-4,6-diene already at a dose of 3.12 γ per day is essentially the same.

Gestation maintenance test

This test is based on the fact that miscarriage, which is the norm in rabbits, is the in the course of the gestation of a cophorectomy

209 025 / U5

should be avoided by appropriate treatment that replaces the ovarian hormones can.

On the 14th day of each gestation, neutered rabbits are used, which are neutered daily from the 13th to Treated by subcutaneous route for the 27th day.

The product is administered in solution in olive oil with the addition of 5% benzyl alcohol. The animals are sacrificed on the 28th day. The foeti are removed, counted, measured and weighed. The number of foeti carried by each rabbit and, if applicable, the number of fetuses are given existing macerated placenta. The latter correspond to miscarriages.

The 17a-methyl-3.20-dioxo-19-nor-pregna-4,9 (10) -diene is administered subcutaneously in daily doses of 0.0125, 0.025 and 0.050 mg per rabbit group administered.

This test is performed in comparison with three groups of pregnant rabbits that are under spayed under the same conditions and those with daily doses of 0.025, 0.050 and 0.100 mg, respectively 3,20-DiOXO-Oa-ChIOr-17 «-acetoxy-pregna-4,6-diene, administered subcutaneously in the same solvent. While the dose of 0.025 mg 3,20-DiOXO-Oa-ChIor-17a-acetoxy-pregna-4,6-diene If a total miscarriage is not prevented, keep the same dose of S ^ O-Dioxo-na-methyl - ^ - nor-pregna-4,9 (10) -diene the gestation in the rabbits was upright in 50% of the cases. '■' '30

The 3.20-dioxo-17a-methyl-19-nor-pregna-4,9 (10) -diene therefore shows an essential gestative Effect already at a dose of 0.025 mg per day.

Claims (3)

Patent claims: 1. 3.20 - Dioxo - 17a - methyl - 19 - nor - pregna-4,9-diene of the formula 35 40 45 2. Process for the preparation of 3,20-dioxo-17a-methyl-19-nor-pregna-4,9-diene of the formula.-., _ characterized in that one a) the 3-CmOr-S-OXO-na-methyl ^ O-benzoyloxy - 4,5 - seco -19 - nor - pregna - 2.9 - dien zürn 3 - chlorine - 5 - oxo - 17a - methyl - 20 - hydroxy-4,5 - seco - 19 - nor - pregna - 2.9 - diene saponified, for 3 - chlorine - 5.20 - dioxo - 17 «- methyl-4,5-seco-19-nor- pregna - 2,9 - diene oxidizes its vinyl chlorine in an acidic medium to form 3,5,20-trioxo-17 «-methyl-4,5-seco-19-nor-pregna-9-ene hydrolyzed, the compound thus obtained is cyclized with the help of an alkaline agent, or that one b) the double bond in the 16-, 17-position des 3-methoxy-20-oxo-19-nor-pregna-1,3,5 (10), 16-tetraene with simultaneous alkylation with the help of an alkali metal and a methyl halide to form 3-methoxy-17a-methyl-20-oxo-19-nor-pregna-l, 3.5 (10) - triens reduced, the compound obtained by the method of D j e r a s s i with an alkali metal in the presence of ammonia to 3-methoxy-17a-methyl-20-hydroxy- 19-nor-pregna-2,5 (10) -diene is reduced, this with a dilute acid to 3-oxo-17a - methyl - 20 -hydroxy -19 - nor - pregna-5 (10) -en hydrolyzed, this by an acid Oxidizing agent to 3,20-Dioxo- Πα-methyl-19-nor-pregna-5 (10) -en oxidized, this Brominated compound with bromine and pyridine and then split off hydrogen bromide. 3. Pharmaceutical compositions, characterized by a. 3,20-Dioxo-17a-methyl-19-nor-pregna-4,9-diene content as an active ingredient.